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Articles, Cellular/Molecular

Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus

Bopanna I. Kalappa, Heun Soh, Kevin M. Duignan, Takeru Furuya, Scott Edwards, Anastasios V. Tzingounis and Thanos Tzounopoulos
Journal of Neuroscience 10 June 2015, 35 (23) 8829-8842; DOI: https://doi.org/10.1523/JNEUROSCI.5176-14.2015
Bopanna I. Kalappa
1Department of Otolaryngology and Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,
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Heun Soh
2Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, and
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Kevin M. Duignan
2Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, and
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Takeru Furuya
3SciFluor Life Sciences, Inc., Cambridge, Massachusetts 02139
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Scott Edwards
3SciFluor Life Sciences, Inc., Cambridge, Massachusetts 02139
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Anastasios V. Tzingounis
2Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, and
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Thanos Tzounopoulos
1Department of Otolaryngology and Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,
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Abstract

Voltage-gated Kv7 (KCNQ) channels are voltage-dependent potassium channels that are activated at resting membrane potentials and therefore provide a powerful brake on neuronal excitability. Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus. Retigabine, a small molecule that activates KCNQ2–5 channels by shifting their voltage-dependent opening to more negative voltages, is an US Food and Drug Administration (FDA) approved anti-epileptic drug. However, recently identified side effects have limited its clinical use. As a result, the development of improved KCNQ2/3 channel activators is crucial for the treatment of hyperexcitability-related disorders. By incorporating a fluorine substituent in the 3-position of the tri-aminophenyl ring of retigabine, we synthesized a small-molecule activator (SF0034) with novel properties. Heterologous expression of KCNQ2/3 channels in HEK293T cells showed that SF0034 was five times more potent than retigabine at shifting the voltage dependence of KCNQ2/3 channels to more negative voltages. Moreover, unlike retigabine, SF0034 did not shift the voltage dependence of either KCNQ4 or KCNQ5 homomeric channels. Conditional deletion of Kcnq2 from cerebral cortical pyramidal neurons showed that SF0034 requires the expression of KCNQ2/3 channels for reducing the excitability of CA1 hippocampal neurons. Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus.

  • KCNQ channels
  • epilepsy
  • tinnitus
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The Journal of Neuroscience: 35 (23)
Journal of Neuroscience
Vol. 35, Issue 23
10 Jun 2015
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Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus
Bopanna I. Kalappa, Heun Soh, Kevin M. Duignan, Takeru Furuya, Scott Edwards, Anastasios V. Tzingounis, Thanos Tzounopoulos
Journal of Neuroscience 10 June 2015, 35 (23) 8829-8842; DOI: 10.1523/JNEUROSCI.5176-14.2015

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Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus
Bopanna I. Kalappa, Heun Soh, Kevin M. Duignan, Takeru Furuya, Scott Edwards, Anastasios V. Tzingounis, Thanos Tzounopoulos
Journal of Neuroscience 10 June 2015, 35 (23) 8829-8842; DOI: 10.1523/JNEUROSCI.5176-14.2015
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Keywords

  • KCNQ channels
  • epilepsy
  • tinnitus

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